Statistical Topic:Ethics and Trial Design*
Elizabeth Garrett-Mayer
August 14, 2009
HCC Journal Club
* Thanks to my colleague Steve Goodman
Outline
Ethics in medical research Equipoise Informed consent RCT of CBC vs. CB RCT of sunitinib vs. placebo
Shalala Statement
Bill Clinton's Secretary of Health and Human Services
Protecting Research Subjects – What Must Be Done (NEJM, 9/14/2000)
The Problems Informed consent is not perfect Too many researchers not adhering to good
clinical practice IRBs under pressure – oversight inadequate Increasing conflicts of interests in CTs
Shalala Statement (cont.)
The Solutions NIH/FDA aggressive effort to improve
education and training Guidelines for informed consent NIH requirement for trial monitoring plans for
small trials and FDA guidelines for DSMBs Clarification of conflict of interest regulations Legislation to penalize in cases of violations of
“important research practices” ($250K/investigator and $1M/institution)
Important Message
Ethical tensions pervade every aspect of design, execution, interpretation, and use of clinical research
Every choice we make about a study has ethical implications, regardless of whether or not we explicitly consider them.
Ethical Theories
Utilitariansim – We should aim for “the good” of a world with collectively great happiness Morality concerns objective assessments of
states of the world and not individual acts
Deontology – We should aim for “the good” of treating people properly: the golden rule of “do unto others…” Morality concerns the rightness of individual
acts, regardless of the states of the world they entail
The tension
Utilitarian One’s chance of getting the best treatment is
highest if one lives in a society where treatment choices are governed by RCTs
Deontologic You want your physician to give you the
treatment s/he and you decide is most likely best for you
However….
Helsinki DeclarationIn medical research on human
subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society
Most Important Principle: Equipoise
Equipoise is the concept that a clinical trial (esp. an RCT) is motivated by a collective uncertainty about the superiority of one treatment versus its alternative (Piantadosi, 2005)
Satisfies the requirement that study participants not be disadvantaged
“At the start of the trial, there must be a state of clinical equipoise regarding the merits of the regimens to be tested, and the trial must be designed in such a way as to make it reasonable that if it is successfully conducted, clinical equipoise will be disturbed.” (Freedman, 1987)
Equipoise
Once equipoise is “disturbed” It is no longer ethical to randomize (or otherwise assign)
patients to less effective therapy If trial is done well:
lack of efficacy should be clear efficacy should be clear should NOT have a situation where we are unsure!
When is it disturbed? interim analysis? early stopping for safety? early stopping for efficacy or futility? end of the study?
Informed Consent
Clinicians, PIs, Co-Is, CTOs, etc. Understand the CTs (for the most part) Understand the risks and benefits
• risks differ by phase• phase I less likely to improve prognosis• phase III is likely to provide standard of care or better
We are very used to the idea of trials (RCTs and others) Patients, generally
Are unfamiliar with clinical research Put trust in their doctors Assume that they will get “the best” treatment when it is
known Do not understand “chance” and “randomization” Assume a trial will help (even Phase I)
Informed Consent: 4 criteria
Is patient capable of giving consent? Protection for those with diminished capacity (children,
prisoners, developmentally disabled, elderly) Recognition of patient vulnerability due to anxiety, or
effects prior to treatment Is consent given freely? “Coercion”
Refusal to offer certain therapies outside of study settings
Change in caregiver due to refusal of consent Is patient given ALL necessary information, including
alternatives? Can patient UNDERSTAND information?
Informed Consent
6th-8th grade reading levelNo “big” wordsShort sentences
Short and sweet vs. long and tiresome?
Conflicts: PI and caregiver?Accrual goals
Ethical issues in RCT of CB vs. CBC in metastatic colorectal cancer
Sufficient investigation of combination a priori? synergistic/overlapping toxicities? strength of evidence of increased efficacy in
phase II study (N=40)? Preliminary data and basis for study design is
from a different ‘similar’ regimen Choice of endpoint: PFS
death progression last follow-up (censored)
Ethical issues in RCT of CB vs. CBC in metastatic colorectal cancer
“Unexpected interaction” between two monoclonal antibodiescould this have been anticipated with
sufficient preliminary data? Interaction in effects on signaling pathway
“subtle interactions in intracellular signaling”
biological basis for combination?
RCTs of new combinations
Interesting contrast: for most studies of A vs. A+Bpatients want combination armequipoise questionable: how can
adding an active agent be worse?sometimes one-sided approach to
testingoften have 2:1 randomization favoring
the combination
Adding cetuximab
Major differences in QoL AND PFSQoL difference not discussed very
muchOverall survival not different
Significant increase in grade 3&4 toxicities attributes to cetuximab
Adding cetuximab: potential problem with interpretation 81 (26%) and 99 (30%) of patients discontinued due to
adverse events in the CB and CBC arms (respectively).
But, at what time did the discontinuations occur? Time to discontinuation is likely important
patients who discontinue earlier are more likely to have earlier progression
current discussion does not address time to discontinuation in two arms
can glean some intuition based on number of cycles and duration of treatment
• median duration (months): 7 CB and 6 CBC• median number cycles: 10 CB and 9 CBC
Controversial topic in phase III trials: placebo arm
Controversial when placebo is not added to some active agent
Example: RCT of Sunitinib in advanced GI stromal tumor
Ethical issues in RCT of Sunitinib
in advanced GI stromal tumor 2:1 ratio of Sutent vs. placebo
Does that make us question equipoise?Is it for patient accrual?
Phase I/II study showed “promising activity”Little responseSignificant stable disease
Ethical issues in RCT of Sunitinib
in advanced GI stromal tumor Cross-over included (but didn’t help) Double-Blinded: maintains equipoise Interim analyses after 141 and 211
progressionsValid designPrevalent problem in “frequentist”
statistics: need to waitAt what point COULD we have
stopped?
Observed Data
What if they had looked at the data earlier in the study?
Why not single arm?
What is standard of care? No 2nd line treatments after failure of imatinib Was this ethically designed? Revised Helsinki Declaration (section 29)
The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic and therapeutic methods. This does not exclude the use of placebo, or no treatment, where no proven prophylactic. diagnostic or therapeutic method exists.
What design would you have felt most comfortable with? as a researcher, which is the best design? would you encourage your family member to go on this trial?